Lynozyfic Drug Information
Generic name: LINVOSELTAMAB-GCPT
Bispecific B Cell Maturation Antigen-directed CD3 T Cell Engager [EPC]
Uses of Lynozyfic
is indicated for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least four prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody. This indication is approved under accelerated approval based on response rate and durability of response . Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s). LYNOZYFIC is a bispecific B-cell maturation antigen (BCMA)‑directed CD3 T-cell engager indicated for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least four prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti‑CD38 monoclonal antibody. This indication is approved under accelerated approval based on response rate and durability of response.
Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).
Dosage & Administration of Lynozyfic
| Step-Up Dosing Schedule | Day 1 |
|---|---|
| Day 8 | Step-up dose 2 |
| Day 15 | First treatment dose |
| Weekly Dosing Schedule | One week after Day 15 treatment dose and once weekly from Week 4 to Week 13 for 10 treatment doses |
| Biweekly (Every 2 Weeks) Dosing Schedule | Week 14 and every 2 weeks thereafter |
| Every 4 Weeks Dosing Schedule | At Week 24 or after and every 4 weeks thereafter |
Side Effects of Lynozyfic
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Relapsed or Refractory Multiple Myeloma The safety of LYNOZYFIC was evaluated in LINKER-MM1 . Patients (n=117) received LYNOZYFIC as step-up doses of 5 mg on Day 1 and 25 mg on Day 8, and the first treatment dose of 200 mg on Day 15. Patients then received 200 mg intravenously once weekly from Week 4 to Week 13, followed by 200 mg every 2 weeks from Week 14. In the Phase 2 portion of the study, patients who achieved and maintained VGPR or better at or after Week 24 and received at least 17 doses of 200 mg were able to receive every 4-week dosing. The median duration of treatment was 47 weeks (range 1, 151); 55% of patients were exposed for 9 months or longer and 36% were exposed for 1 year or longer.
The median age of patients who received LYNOZYFIC was 70 years (range: 37 to 91 years); 55% were male; 71% were White, 17% were Black or African American, and 9% were Asian. Serious adverse reactions occurred in 74% of patients who received LYNOZYFIC. Serious adverse reactions that occurred in >5% of patients included cytokine release syndrome (27%), pneumonia (13%), COVID-19 (7%), and acute kidney injury (5%). Fatal adverse reactions occurred in 7% of patients, and included sepsis (3.4%), chronic kidney disease (0.9%), pneumonia (0.9%), tumor lysis syndrome (0.9%), and encephalopathy (0.9%). Permanent discontinuation of LYNOZYFIC due to adverse reactions occurred in 16% of patients. Adverse reactions leading to discontinuation that occurred in at least 2 patients included sepsis, pneumonia, and encephalopathy.
Dosage interruptions or delays of LYNOZYFIC due to adverse reactions occurred in 74% of patients. Adverse reactions which required a dosage interruption or delay in >10% of patients included neutropenia (29%), upper respiratory tract infection (18%), pneumonia (15%), and COVID-19 infection (11%). The most common adverse reactions (≥20%) were musculoskeletal pain, cytokine release syndrome, cough, upper respiratory tract infection, diarrhea, fatigue, pneumonia, nausea, headache, and dyspnea. The most common Grade 3 to 4 laboratory abnormalities (≥30%) were decreased lymphocyte count, decreased neutrophil count, decreased hemoglobin, and decreased white blood cell count.
Table 7 summarizes the adverse reactions in LINKER-MM1. Table 7: Adverse Reactions (≥10%) in Patients with Relapsed or Refractory Multiple Myeloma Who Received LYNOZYFIC in LINKER-MM1 Adverse Reaction LYNOZYFIC (N=117) All Grades (%) Grade 3 or 4 (%) Musculoskeletal and connective tissue disorders Musculoskeletal pain Includes other related terms. 53
Only Grade 3 adverse reactions occurred. Immune system disorders Cytokine release syndrome
46
Hypogammaglobulinemia 13 0.9 Respiratory, thoracic and mediastinal disorders Cough 39 0 Dyspnea
21
Nasal congestion 16 0 Infections and infestations Upper respiratory tract infection 35
6 Pneumonia Pneumonia includes atypical pneumonia, COVID-19 pneumonia, PJP, pneumonia, pneumonia cytomegaloviral, pneumonia fungal, pneumonia influenzal, and pneumonia viral., Includes fatal outcome. 28 21 COVID-19 17 5 Urinary tract infections 16 8 Sepsis 10 6 Gastrointestinal disorders Diarrhea 35
Nausea 23 0 Vomiting 19 0 Constipation 17 0 General disorders and
administration site conditions Fatigue 34 0 Edema 19
Pyrexia 17 0 Nervous system disorders Headache 22 0.9 Encephalopathy, Encephalopathy includes
agitation, amnesia, cognitive disorder, confusional state, delirium, depressed level of consciousness, encephalopathy (including hyperammonemic and toxic encephalopathy), irritability, lethargy, memory impairment, mental status changes, somnolence, and excludes ICANS. 18
Sensory Neuropathy 13 0.9 Metabolism and nutrition disorders Decreased appetite 15 0.9
Skin and subcutaneous tissue disorders Rash Rash includes dermatitis acneiform, dermatitis contact, drug eruption, erythema, rash, rash erythematous, rash maculo-papular, rash pruritic, and stasis dermatitis. 15
Psychiatric disorders Insomnia 13 0 Vascular disorders Hypertension 10 4.3 Clinically significant
adverse reactions that occurred in <10% of patients treated with LYNOZYFIC included IRR, motor dysfunction, febrile neutropenia, ICANS, CMV infection, and PML. Table 8 summarizes the laboratory abnormalities in LINKER-MM1. Table 8: Select Laboratory Abnormalities (≥5% for Grade 3 or 4) That Worsened from Baseline in Patients with Multiple Myeloma Treated with LYNOZYFIC in LINKER-MM1 Laboratory Abnormality Laboratory tests were graded according to NCI-CTCAE (National Cancer Institute Common Terminology Criteria for Adverse Events) Version 5.0. LYNOZYFIC (N=117) The denominator used to calculate the rate varied from 106 to 117 based on the number of patients with a baseline value and at least one post-treatment value. All Grades (%) Grades 3 or 4 (%) Hematology Lymphocyte count decreased 97 92 Hemoglobin decreased 72 42 Platelet count decreased 64 19 White blood cell count decreased 63 31 Neutrophil count decreased 62 47 Chemistry Aspartate aminotransferase increased 61 10 Phosphorus decreased 55 24 Creatinine increased 47 7 Alanine aminotransferase increased 46 6
Warnings & Cautions for Lynozyfic
Cytokine Release Syndrome (CRS)
LYNOZYFIC can cause cytokine release syndrome (CRS), which can be serious or life-threatening. In LINKER-MM1, CRS occurred in 46% (54/117) of patients who received LYNOZYFIC at the recommended dose, with Grade 1 CRS occurring in 35% (41/117) of patients, Grade 2 in 10% (12/117), and Grade 3 in 0.9% (1/117) . Thirty-eight percent (45/117) of patients had CRS following step-up dose 1, including 1 patient who experienced Grade 3 CRS; 8% (9/117) had an initial CRS event following a subsequent dose. Seventeen percent (19/113) of patients developed CRS after step-up dose 2, 10% (11/111) developed CRS after the first full 200 mg dose of LYNOZYFIC, and 3.6% (4/110) developed CRS after the second full dose.
Recurrent CRS occurred in 20% (23/117) of patients. The median time to onset of CRS from the end of infusion was 11 (range: -1 to 184) hours after the most recent dose with a median duration of 15 (range: 1 to 76) hours. Clinical signs and symptoms of CRS included, but were not limited to pyrexia, chills, hypoxia, tachycardia, and hypotension.
Administer pretreatment medications and initiate therapy according to LYNOZYFIC step-up dosing to reduce the incidence and severity of CRS. Monitor patients for signs and symptoms of CRS after infusion. Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur. At the first sign of CRS, immediately evaluate patients for hospitalization, manage per current practice guidelines, and administer supportive care; withhold LYNOZYFIC until CRS resolves and modify the next dose or permanently discontinue LYNOZYFIC based on severity.
Infusion Related Reactions Infusion-related reactions (IRR) may be clinically indistinguishable from manifestations of CRS. In the patients who were treated with the recommended step-up dosing regimen and pretreatment medications , the rate of IRR was 9%. For IRR, interrupt or slow the rate of infusion or permanently discontinue LYNOZYFIC based on severity of reaction . LYNOZYFIC is available only through a restricted program under a REMS .
Neurologic Toxicity, including Immune Effector Cell-Associated Neurotoxicity Syndrome
LYNOZYFIC can cause serious or life-threatening neurologic toxicity, including immune effector cell-associated neurotoxicity syndrome (ICANS). In LINKER-MM1, neurologic toxicity occurred in 54% of patients, with Grade 3 or 4 neurologic toxicity occurring in 8%, at the recommended dose. Neurologic toxicities included ICANS, depressed level of consciousness, encephalopathy, and toxic encephalopathy. ICANS occurred in 8% of patients who received LYNOZYFIC with the recommended dosing regimen, including Grade 3 events in 2.6%. Most patients experienced ICANS following step-up dose 1 (5%). Two patients (1.8%) experienced initial ICANS following step-up dose 2 and one patient developed the first occurrence of ICANS following a subsequent full dose of LYNOZYFIC. Recurrent ICANS occurred in one patient.
The median time to onset of ICANS was 1 (range: 1 to 4) day after the most recent dose with a median duration of 2 (range: 1 to 11) days. The onset of ICANS can be concurrent with CRS, following resolution of CRS, or in the absence of CRS. The most common clinical signs and symptoms of ICANS are confusion, depressed level of consciousness, and lethargy. Monitor patients for signs and symptoms of neurologic toxicity during treatment.
At the first sign of neurologic toxicity, including ICANS, immediately evaluate the patient; provide supportive therapy and consider further management per current practice guidelines. Withhold LYNOZYFIC until ICANS resolves and modify the next dose or permanently discontinue LYNOZYFIC based on severity . Counsel patients to seek immediate medical attention should signs or symptoms of neurologic toxicity occur at any time. Due to the potential for neurologic toxicity, including ICANS, patients receiving LYNOZYFIC are at risk of confusion and depressed consciousness.
Advise patients to refrain from driving, or operating heavy or potentially dangerous machinery, for 48 hours after completion of each of the step-up doses and in the event of new onset of any neurological symptoms, until symptoms resolve. LYNOZYFIC is available only through a restricted program under a REMS .
LYNOZYFIC
REMS LYNOZYFIC is available only through a restricted program under a REMS called the LYNOZYFIC REMS because of the risks of CRS and neurologic toxicity, including ICANS . Notable requirements of the LYNOZYFIC REMS include the following: Prescribers must be certified with the program by enrolling and completing training. Prescribers must counsel patients receiving LYNOZYFIC about the risk of CRS and neurologic toxicity, including ICANS, and provide patients with LYNOZYFIC Patient Wallet Card. Pharmacies and healthcare settings that dispense LYNOZYFIC must be certified with the LYNOZYFIC REMS program and must verify prescribers are certified through the LYNOZYFIC REMS program.
Wholesalers and distributors must only distribute LYNOZYFIC to certified pharmacies or healthcare settings. Further information about the LYNOZYFIC REMS program is available at lynozyficREMS.com or by telephone at 1-855-212-6391.
Infections
LYNOZYFIC can cause serious, life-threatening, or fatal infections. In patients who received LYNOZYFIC at the recommended dose in LINKER-MM1, serious infections, including opportunistic infections, occurred in 42% of patients, with Grade 3 or 4 infections in 38% and fatal infections in 4% . The most common serious infection reported (≥10%) were pneumonia and sepsis. Two cases of progressive multifocal leukoencephalopathy (PML) occurred in patients receiving LYNOZYFIC. Monitor patients for signs and symptoms of infection and immunoglobulin levels prior to and during treatment with LYNOZYFIC and treat appropriately.
Administer prophylactic antimicrobials, antibiotics, antifungals, antivirals, vaccines, and subcutaneous or intravenous immunoglobulin (IVIG) according to guidelines, including prophylaxis for PJP and herpesviruses . Withhold LYNOZYFIC or consider permanent discontinuation of LYNOZYFIC based on severity of the infection .
Neutropenia
LYNOZYFIC can cause neutropenia and febrile neutropenia. In patients who received LYNOZYFIC at the recommended dose in LINKER-MM1, decreased neutrophil count occurred in 62% of patients with Grade 3 or 4 decreased neutrophil count in 47%. Febrile neutropenia occurred in 8% of patients . Monitor complete blood cell counts at baseline and periodically during treatment and provide supportive care per local guidelines. Monitor patients with neutropenia for signs of infection.
Withhold LYNOZYFIC based on severity .
Hepatotoxicity
LYNOZYFIC can cause hepatotoxicity. In LINKER-MM1, elevated ALT occurred in 46% of patients, with Grade 3 or 4 ALT elevation occurring in 6%; elevated AST occurred in 61% of patients, with Grade 3 or 4 AST elevation occurring in 10% of patients who received the recommended dose. Grade 3 or 4 total bilirubin elevations occurred in 1.7% of patients . Liver enzyme elevation can occur with or without concurrent CRS. Monitor liver enzymes and bilirubin at baseline and during treatment as clinically indicated.
Withhold LYNOZYFIC or consider permanent discontinuation of LYNOZYFIC based on severity.
Embryo-Fetal Toxicity
Based on its mechanism of action, LYNOZYFIC may cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment with LYNOZYFIC and for 3 months after the last dose .
Drug Interactions with Lynozyfic
Effects of
LYNOZYFIC on Other Drugs Certain CYP substrates Monitor for toxicity unless otherwise recommended in the Prescribing Information of certain CYP substrates where minimal changes in the concentration may lead to serious adverse reactions when used concomitantly with LYNOZYFIC. Linvoseltamab-gcpt causes the release of cytokines that may suppress cytochrome P450 (CYP) enzyme activity. Concomitant use with LYNOZYFIC increases CYP substrate exposure which may increase the risk of adverse reactions related to these substrates. Increased CYP substrate exposure is more likely to occur from initiation of the LYNOZYFIC step-up dosing schedule up to 14 days after the first 200 mg dose, and during and after CRS .
Pregnancy Safety for Lynozyfic
Pregnancy Risk Summary Based on the mechanism of action, LYNOZYFIC may cause fetal harm when administered to a pregnant woman . There are no available data on the use of LYNOZYFIC in pregnant women to evaluate for a drug associated risk. No animal reproductive or developmental toxicity studies have been conducted with LYNOZYFIC. Linvoseltamab-gcpt causes T-cell activation and cytokine release; immune activation may compromise pregnancy maintenance. In addition, based on the finding of B-cell depletion in non-pregnant animals, linvoseltamab-gcpt can cause B-cell lymphocytopenia in infants exposed to linvoseltamab-gcpt in-utero.
Human immunoglobulin (IgG) is known to cross the placenta after the first trimester of pregnancy; therefore, linvoseltamab-gcpt has the potential to be transmitted from the mother to the developing fetus. Advise women of the potential risk to the fetus. LYNOZYFIC is associated with hypogammaglobulinemia, therefore, assessment of immunoglobulin levels in newborns of mothers treated with LYNOZYFIC should be considered.
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Pediatric Use of Lynozyfic
Pediatric Use The safety and effectiveness of LYNOZYFIC have not been established in pediatric patients.
Clinical Studies of Lynozyfic
Relapsed or Refractory Multiple Myeloma
The efficacy of LYNOZYFIC was evaluated in patients with relapsed or refractory multiple myeloma in an open-label, multi-center, multi-cohort study: LINKER-MM1 (NCT03761108). The study included patients who had previously received at least 3 prior therapies, including a proteasome inhibitor (PI), an immunomodulatory agent (IMiD), and an anti-CD38 antibody. The study included patients with Eastern Cooperative Oncology Group (ECOG) score of 0 or 1 and adequate baseline hematologic (absolute neutrophil count > 1 × 10 9 /L, platelet count > 50 × 10 9 /L, hemoglobin level >8 g/dL), renal (CrCL > 30 mL/min), and hepatic (AST and ALT ≤ 2.5 × ULN, total bilirubin ≤ 1.5 × ULN, alkaline phosphatase ≤ 2.5 × ULN) function. The study excluded patients with known multiple myeloma brain lesions or meningeal involvement, history of a neurodegenerative condition, history of seizure within 12 months prior to study enrollment, active infection, a history of an allogeneic or autologous stem cell transplantation within 12 weeks, prior BCMA-directed bispecific antibody therapy, prior bispecific T-cell engaging therapy, or prior BCMA CAR-T cell therapy.
Patients received a step-up dose of 5 mg on Day 1, 25 mg on Day 8, and the first treatment dose of 200 mg on Day 15 of LYNOZYFIC by intravenous infusion. Then, patients received 200 mg of LYNOZYFIC weekly from Week 4 to Week 13, followed by 200 mg every other week thereafter. After at least 24 weeks, the Phase 2 patients who achieved a very good partial response (VGPR) or greater received 200 mg of LYNOZYFIC every 4 weeks.
Patients were treated until disease progression or unacceptable toxicity. The efficacy population included 80 patients who had received at least four prior lines of therapy. The median age was 71 (range: 37 to 83) years with 30% of patients 75 years or older; 64% were male and 36% were female; 69% were White, 14% were Black or African American, 13% were Asian, and 2.5% were Hispanic/Latino.
The International Staging System (ISS) at study entry was Stage I in 39%, Stage II in 36%, and Stage III in 19%. High-risk cytogenetics (presence of del(17p), t(4;14) and t(14;16)) were present in 40% of patients. Eighteen percent of patients had extramedullary disease at baseline. The median number of prior lines of therapy was 5 (range: 4 to 13); 83% of patients were refractory to the last line of therapy.
Sixty-five percent of patients received prior stem cell transplantation. Seventy-nine percent of patients were triple-class refractory (refractory to a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody). Thirteen percent of patients were previously treated with a BCMA antibody-drug conjugate. Efficacy was established based on objective response rate (ORR) as determined by blinded independent review committee (IRC), as measured using the International Myeloma Working Group (IMWG) criteria (see Table 10 ). The median time to first response was 0.95 months (range: 0.5 to 6 months). With a median follow-up of 11.3 months among responders, the estimated duration of response (DOR) rate was 89% (95% CI: 77, 95) at 9 months and 72% (95% CI: 54, 84) at 12 months.
Table 10: Efficacy Results for LINKER-MM1 Efficacy Endpoints LYNOZYFIC N=80 CI=confidence interval; NE=not estimable Objective Response Rate (ORR) % (n) 70% (95% CI) Complete response (CR) or better, % (n) 45% (95% CI) Stringent complete response (sCR), % (n) 39% Complete response (CR), % (n) 6% Very good partial response (VGPR) % (n) 19% Partial response (PR), % (n) 6% Duration of Response (DOR) Based on Kaplan-Meier estimation. Median, months (95% CI) NR (12, NE)
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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